Access to the nucleus of the host cell is a prerequisite for the replication of many viruses. Herpes simplex virus-1 (HSV-1) consists of a viral capsid that is too large to enter the nucleus itself. Therefore, HSV-1's double-stranded DNA genome is introduced into the nucleus of the host cell in a tightly regulated uncoating step. The viral-host interactions that control this key step in the herpes life cycle remain largely unknown. The goal of the proposed research is to determine how the herpes capsid docks at the cell's nuclear pore, uncoats, and delivers its DNA into the nucleus. Since viruses often exploit normal cellular processes, recent advances in our understanding of general nuclear import will be used to study the specific problem of herpes genome nuclear entry. Three approaches - cell biological, biochemical, and genetic - are proposed for defining the viral and cellular factors that mediate this process. Studying these important viral-host interactions will bring us closer to understanding a long-standing mystery in virology: why do incoming capsids readily uncoat, while newly-assembled outgoing capsids do not? In addition, this work will further our general understanding of nuclear transport. Finally, results of the proposed experiments may lead to the development of more effective antiviral therapies as well as more efficient gene delivery systems. The proposed project, to be conducted in Ari Helenius's lab at Yale University School of Medicine, will significantly enhance my experience as a physician/scientist, since it offers training in both virology and cell biology. Furthermore, the Research Career Award will provide the necessary training for me to reach my long-term goal: a career in academic medicine, with primary emphasis on an independent research program that will arise from this work with Dr. Helenius.